PMID- 33123756
OWN - NLM
STAT- MEDLINE
DCOM- 20210504
LR  - 20240427
IS  - 1432-0851 (Electronic)
IS  - 0340-7004 (Print)
IS  - 0340-7004 (Linking)
VI  - 70
IP  - 5
DP  - 2021 May
TI  - Impact of tumor heterogeneity and microenvironment in identifying neoantigens in 
      a patient with ovarian cancer.
PG  - 1189-1202
LID - 10.1007/s00262-020-02764-9 [doi]
AB  - Identification of neoepitopes as tumor-specific targets remains challenging, 
      especially for cancers with low mutational burden, such as ovarian cancer. To 
      identify mutated human leukocyte antigen (HLA) ligands as potential targets for 
      immunotherapy in ovarian cancer, we combined mass spectrometry analysis of the 
      major histocompatibility complex (MHC) class I peptidomes of ovarian cancer cells 
      with parallel sequencing of whole exome and RNA in a patient with high-grade 
      serous ovarian cancer. Four of six predicted mutated epitopes capable of binding 
      to HLA-A*02:01 induced peptide-specific T cell responses in blood from healthy 
      donors. In contrast, all six peptides failed to induce autologous 
      peptide-specific response by T cells in peripheral blood or tumor-infiltrating 
      lymphocytes from ascites of the patient. Surprisingly, T cell responses against a 
      low-affinity p53-mutant Y220C epitope were consistently detected in the patient 
      with either unprimed or in vitro peptide-stimulated T cells even though the 
      patient's primary tumor did not bear this mutation. Our results demonstrated that 
      tumor heterogeneity and distinct immune microenvironments within a patient should 
      be taken into consideration for identification of immunogenic neoantigens. T cell 
      responses to a driver gene-derived p53 Y220C mutation in ovarian cancer warrant 
      further study.
FAU - Dao, Tao
AU  - Dao T
AD  - Molecular Pharmacology Program, SKI, Memorial Sloan Kettering Cancer Center, New 
      York, NY, USA.
FAU - Klatt, Martin G
AU  - Klatt MG
AD  - Molecular Pharmacology Program, SKI, Memorial Sloan Kettering Cancer Center, New 
      York, NY, USA.
FAU - Korontsvit, Tatyana
AU  - Korontsvit T
AD  - Molecular Pharmacology Program, SKI, Memorial Sloan Kettering Cancer Center, New 
      York, NY, USA.
FAU - Mun, Sung Soo
AU  - Mun SS
AD  - Molecular Pharmacology Program, SKI, Memorial Sloan Kettering Cancer Center, New 
      York, NY, USA.
FAU - Guzman, Sean
AU  - Guzman S
AD  - Molecular Pharmacology Program, SKI, Memorial Sloan Kettering Cancer Center, New 
      York, NY, USA.
FAU - Mattar, Marissa
AU  - Mattar M
AD  - Molecular Pharmacology Program, SKI, Memorial Sloan Kettering Cancer Center, New 
      York, NY, USA.
FAU - Zivanovic, Oliver
AU  - Zivanovic O
AD  - Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer 
      Center, New York, NY, USA.
AD  - Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, 
      NY, USA.
FAU - Kyi, Chrisann K
AU  - Kyi CK
AD  - Gynecological Medical Oncology Service, Department of Medicine, Memorial Sloan 
      Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
FAU - Socci, Nicholas D
AU  - Socci ND
AD  - Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - O'Cearbhaill, Roisin E
AU  - O'Cearbhaill RE
AUID- ORCID: 0000-0001-8217-4554
AD  - Gynecological Medical Oncology Service, Department of Medicine, Memorial Sloan 
      Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. 
      ocearbhr@mskcc.org.
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY, USA. 
      ocearbhr@mskcc.org.
AD  - National University of Ireland, Galway, Ireland. ocearbhr@mskcc.org.
FAU - Scheinberg, David A
AU  - Scheinberg DA
AD  - Molecular Pharmacology Program, SKI, Memorial Sloan Kettering Cancer Center, New 
      York, NY, USA. scheinbd@mskcc.org.
AD  - Gynecological Medical Oncology Service, Department of Medicine, Memorial Sloan 
      Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. 
      scheinbd@mskcc.org.
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY, USA. 
      scheinbd@mskcc.org.
AD  - Experimental Therapeutics Center, Memorial Sloan Kettering Cancer Center, 1275 
      York Avenue, New York, NY, 10065, USA. scheinbd@mskcc.org.
LA  - eng
GR  - R35 CA241894/CA/NCI NIH HHS/United States
GR  - P01 CA023766/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - CA55349/CA/NCI NIH HHS/United States
GR  - CA23766/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20201029
PL  - Germany
TA  - Cancer Immunol Immunother
JT  - Cancer immunology, immunotherapy : CII
JID - 8605732
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-A*02:01 antigen)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - Antigens, Neoplasm/genetics/*metabolism
MH  - Cells, Cultured
MH  - Epitopes, T-Lymphocyte/genetics/*metabolism
MH  - Female
MH  - HLA-A2 Antigen/genetics/*metabolism
MH  - Humans
MH  - Immunotherapy, Adoptive/*methods
MH  - Middle Aged
MH  - Mutation/*genetics
MH  - Neoplasm Staging
MH  - Ovarian Neoplasms/*immunology
MH  - T-Lymphocytes/*immunology
MH  - Tumor Microenvironment
MH  - Tumor Suppressor Protein p53/genetics/*metabolism
MH  - Exome Sequencing
PMC - PMC8053669
MID - NIHMS1642516
OTO - NOTNLM
OT  - Immunotherapy
OT  - Mass spectrometry
OT  - Neoepitopes
OT  - Ovarian cancer
OT  - Parallel sequencing
OT  - T cell response
COIS- David Scheinberg is on the advisory board of, has received consulting fees from, 
      and/or has equity in Progenics Pharmaceuticals, Sellas, KLUS, Iovance 
      Biotherapeutics, Inc., Pfizer, Actinium Pharmaceuticals, Inc., OncoPep, and 
      Eureka Therapeutics. Tao Dao has equity in Eureka Therapeutics. Dr O'Cearbhaill's 
      institution receives funding for clinical research that she is leading from 
      Celgene/Juno, Tesaro/GSK, Ludwig Cancer Institute, Abbvie, Regeneron, TCR2 
      Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, 
      Genmab Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, and the 
      Gynecologic Oncology Foundation. Dr O'Cearbhaill has served on a once-off 
      advisory board for Regeneron, Genmab Therapeutics, and GSK. All other authors 
      declare no conflict or competing interests.
EDAT- 2020/10/31 06:00
MHDA- 2021/05/05 06:00
PMCR- 2020/10/29
CRDT- 2020/10/30 05:56
PHST- 2020/07/24 00:00 [received]
PHST- 2020/10/15 00:00 [accepted]
PHST- 2020/10/31 06:00 [pubmed]
PHST- 2021/05/05 06:00 [medline]
PHST- 2020/10/30 05:56 [entrez]
PHST- 2020/10/29 00:00 [pmc-release]
AID - 10.1007/s00262-020-02764-9 [pii]
AID - 2764 [pii]
AID - 10.1007/s00262-020-02764-9 [doi]
PST - ppublish
SO  - Cancer Immunol Immunother. 2021 May;70(5):1189-1202. doi: 
      10.1007/s00262-020-02764-9. Epub 2020 Oct 29.